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Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma ( n  = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response. Analysis of fully clinically annotated and sequenced melanoma tumor samples collected before anti-PD1 treatment suggests that determinants of response differ on the basis of previous anti-CTLA4 therapy, and that tumor mutational burden may not be a strong predictor of response across melanoma subtypes.

The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

Monoclonal antibodies directed against cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.

Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8 + T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making. IFNγ secretion by CD8 + T cells is critical for immunotherapy efficacy. In this study, the authors show that melanoma patients can become resistant to immunotherapy by acquiring chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2.

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8 months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed. Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. ClinicalTrials.gov NCT01355120.

Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous malignancy. Immune checkpoint inhibition (ICI) with PD-(L)1 blockade has significantly improved treatment outcomes in metastatic disease. In patients with primary resistance to PD-(L)1 inhibition, a high overall response rate (ORR) of 50% to later-line ipilimumab plus nivolumab (IPI/NIVO) has been demonstrated. However, clinical data on patients with progression after an initial response to IPI/NIVO are still lacking. Clinical data of three metastatic MCC patients who were re-exposed to IPI/NIVO after progression were retrospectively evaluated. Two of the three patients showed primary resistance to avelumab with progressive disease, while one patient showed complete response (according to RECIST V.1.1). All three patients received combined ICI with IPI/NIVO as subsequent therapy, resulting in an ORR of ∼ 67%. However, all three patients progressed during follow-up and were re-exposed to IPI/NIVO. With a follow-up period ranging from 6.5 to 37.1 months, no PFS event has been detected. ORR for IPI/NIVO re-exposition was equal to that of initial IPI/NIVO treatment. In this retrospective follow-up analysis, we observed a response rate of 67% and long-lasting responses after re-exposition to combined ICI in metastatic MCC patients with progression after initial response or disease control upon their first IPI/NIVO treatment. An important observation from this small analysis is that primary resistance to PD-L1 inhibition may result in a better response to IPI/NIVO.

Recent years have been witnessing a substantial improvement in the accuracy of skin cancer classification using convolutional neural networks (CNNs). CNNs perform on par with or better than dermatologists with respect to the classification tasks of single images. However, in clinical practice, dermatologists also use other patient data beyond the visual aspects present in a digitized image, further increasing their diagnostic accuracy. Several pilot studies have recently investigated the effects of integrating different subtypes of patient data into CNN-based skin cancer classifiers. This systematic review focuses on the current research investigating the impact of merging information from image features and patient data on the performance of CNN-based skin cancer image classification. This study aims to explore the potential in this field of research by evaluating the types of patient data used, the ways in which the nonimage data are encoded and merged with the image features, and the impact of the integration on the classifier performance. Google Scholar, PubMed, MEDLINE, and ScienceDirect were screened for peer-reviewed studies published in English that dealt with the integration of patient data within a CNN-based skin cancer classification. The search terms skin cancer classification, convolutional neural network(s), deep learning, lesions, melanoma, metadata, clinical information, and patient data were combined. A total of 11 publications fulfilled the inclusion criteria. All of them reported an overall improvement in different skin lesion classification tasks with patient data integration. The most commonly used patient data were age, sex, and lesion location. The patient data were mostly one-hot encoded. There were differences in the complexity that the encoded patient data were processed with regarding deep learning methods before and after fusing them with the image features for a combined classifier. This study indicates the potential benefits of integrating patient data into CNN-based diagnostic algorithms. However, how exactly the individual patient data enhance classification performance, especially in the case of multiclass classification problems, is still unclear. Moreover, a substantial fraction of patient data used by dermatologists remains to be analyzed in the context of CNN-based skin cancer classification. Further exploratory analyses in this promising field may optimize patient data integration into CNN-based skin cancer diagnostics for patients' benefits.

BackgroundThe incidence of severe immune-related hepatitis (irHepatitis) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 under combination therapy with ipilimumab and nivolumab ranges from 15% to 20%. Current clinical guidelines recommend initiating treatment with systemic corticosteroids, followed by second-line immunosuppressants such as mycophenolate mofetil. In contrast, the use of the tumor necrosis factor-α antibody infliximab—commonly administered for other immune-related adverse events such as colitis—is generally not recommended for irHepatitis. A recent single-center study, however, reported the use of infliximab for steroid-refractory irHepatitis in 10 patients without signs of infliximab-associated hepatotoxicity and overall favorable efficacy.This multicenter retrospective analysis aimed to evaluate the safety and efficacy of infliximab in patients with steroid-refractory irHepatitis.MethodsA total of 28 patients with advanced cutaneous melanoma and irHepatitis during immune checkpoint inhibitor (ICI) therapy were included from five university hospitals in Germany and one in Belgium. Of these, 27 patients were in American Joint Committee on Cancer stage IV (8th edition).ResultsAll patients received ipilimumab plus nivolumab. The Eastern Cooperative Oncology Group performance status was 0 in 75.0% of patients, and nearly all (27/28) developed severe irHepatitis of CTCAE grade 3 or 4 (V.5.0). The median time to onset of irHepatitis was 46 days after first ICI administration. 96.4% of patients were initially treated with systemic corticosteroids. The median interval between onset of irHepatitis and the first dose of infliximab was 23 days. Infliximab was administered intravenously at a dose of 5 mg/kg. 22 patients received one dose, while 6 patients received two doses. In 82.1% of patients, corticosteroids were tapered to less than 5 mg prednisolone equivalent within a median period of 75 days. Clinical remission for irHepatitis (≤CTCAE grade 1) was achieved in 92.9% of patients and was reached after a median time of 21 days following the first infliximab administration. During a median follow-up of 349 days, no deaths or drug-induced liver injury attributable to infliximab were observed.ConclusionIn this retrospective analysis, infliximab appeared to be effective and safe for the treatment of steroid-refractory irHepatitis, with no evidence of hepatotoxicity.

The immunopeptidome is constantly monitored by T cells to detect foreign or aberrant HLA peptides. It is highly dynamic and reflects the current cellular state, enabling the immune system to recognize abnormal cellular conditions, such as those present in cancer cells. To precisely determine how changes in cellular processes, such as those induced by drug treatment, affect the immunopeptidome, quantitative immunopeptidomics approaches are essential. To meet this need, we developed a pulsed SILAC-based method for quantitative immunopeptidomics. Metabolic labeling with lysine, arginine, and leucine enabled isotopic labeling of nearly all HLA peptides across all allotypes (> 90% on average). We established a data analysis workflow that integrates the sequencing-based tool Peptide-PRISM for comprehensive HLA peptide identification with MaxQuant for accurate quantification. We employed this strategy to explore the modulation of the immunopeptidome upon MAPK pathway inhibition (MAPKi) and to investigate alterations associated with early cellular responses to inhibitor treatment and acquired resistance to MAPKi. Our analyses demonstrated significant changes in the immunopeptidome early during MAPKi treatment and in the resistant state. Moreover, we identified putative tumor-specific cryptic HLA peptides linked to these processes that might represent exploitable targets for cancer immunotherapy. We have developed a new mass spectrometric approach that allowed us to investigate the effects of common MAPK inhibitors on the immunopeptidome of melanoma cells. This finally led to the discovery of new potential targets for cancer immunotherapy.

Background Adjuvant treatment with PD-1 inhibitors for 12 months has been the established standard of care for patients with resected stage IIB-IV cutaneous melanoma. In other solid tumours (e.g. breast and colorectal), a shorter duration of adjuvant chemotherapy has been shown to be non-inferior with improved toxicity profile. More recently, neoadjuvant immunotherapy with immune checkpoint inhibitors for clinically detectable stage III and stage IV disease has been introduced. There is no clear biological rationale for the chosen duration, and no studies have investigated duration of adjuvant treatment with immune checkpoint inhibitors. A reduced duration of adjuvant therapy could lead to less toxicity from reduced drug exposure, patients returning to normal life sooner, significantly lower drug costs and better healthcare resource utilization. There remains significant interest from patients and clinicians to address this important question. Methods Grand SLAM is a prospective phase III randomised, controlled international multi-centre non-inferiority study. The primary objective is to investigate if short (6 months) has equal efficacy as long (12 months) duration of (neo-)adjuvant immune checkpoint inhibition in relation to distant metastasis-free survival and relapse-free survival at landmark analysis at 2 years. After radical surgery of stage IIB-C, III or IV cutaneous melanoma, patients are randomly assigned 1:1 to short or long adjuvant treatment with either nivolumab or pembrolizumab. Patients who have received neoadjuvant treatment with major pathological response are excluded. The sample size of 1,880 patients was determined based on a non-inferiority margin of 4%, a significance level of 0.045 and 80% statistical power. An interim analysis will be conducted when 2/3 of patients are accrued. Biomarkers and the role of food supplements for relapse (MelKo) will be investigated in prespecified substudies. Discussion This is the first randomised study to assess a shorter duration of adjuvant anti PD-1 antibody in cutaneous melanoma patients. As of March 2026, the study is recruiting patients in the Nordic countries. Centres in other countries will open shortly. Trial registration NCT06488482. Date of registration: 2024-06-10.